A soluble α-synuclein construct forms a dynamic tetramer

Wei Wang, Iva Perovic, Johnathan Chittuluru, Alice Kaganovich, Linh T.T. Nguyen, Jingling Liao, Jared R. Auclair, Derrick Johnson, Anuradha Landeru, Alana K. Simorellis, Shulin Ju, Mark R. Cookson, Francisco J. Asturias, Jeffrey N. Agar, Brian N. Webb, Chul Hee Kang, Dagmar Ringe, Gregory A. Petsko, Thomas C. Pochapsky, Quyen Q. Hoang

Research output: Contribution to journalArticle

277 Scopus citations

Abstract

A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 Nterminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated "hairpin" structure of α-synuclein.

Original languageEnglish (US)
Pages (from-to)17797-17802
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number43
DOIs
StatePublished - Oct 25 2011

Keywords

  • Dynamic structure
  • Helical
  • Heteronuclear single-quantum coherence
  • NMR
  • Parkinson's disease

ASJC Scopus subject areas

  • General

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  • Cite this

    Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C. H., Ringe, D., Petsko, G. A., Pochapsky, T. C., & Hoang, Q. Q. (2011). A soluble α-synuclein construct forms a dynamic tetramer. Proceedings of the National Academy of Sciences of the United States of America, 108(43), 17797-17802. https://doi.org/10.1073/pnas.1113260108